tbuckley/cabot-search huggingface dataset:
SWK-08. Implementing awareness practice in Neuro-Oncology
Authors: Veronica DeRosa
Journal: Neuro-Oncology (2022)

Abstract Awareness practices are mind-body medicine techniques that help quiet the chatter of worry, fear, or the "to-do list" in the mind and allows the individual to experience calm and focus. Neuro-Oncology families undergo a variety of stressors that increase the "mind chatter" once their child is diagnosed with a brain tumor. These families not only have to manage the day-to-day tasks of family life, but they are thrust into a world of uncertainty which often can breed anxiety. To help mitigate the stress and anxiety that Neuro-Oncology families undergo, sessions focusing on awareness practices were offered to parent caregivers once a week for 15-20 minutes via the Zoom platform. The goal of these sessions was to offer respite from mental and emotional challenges brought on by the cancer diagnosis and the COVID 19 pandemic. Separate sessions were also offered to Oncology nurse case managers to help decrease compassion fatigue as these nurses also walk alongside oncology families through the cancer journey providing advocacy and patient/family support. Breath awareness, imagery, and meditation practices were used during the sessions to activate the body's relaxation response to allow for rest and restoration.
Urinary human papilloma virus infection and bladder cancer risk: A systematic review and a prisma-compliant meta-analysis
Authors: D. Garcia-Rojo, J. Muñoz-Rodriguez, C. Centeno, A. Dominguez, A. Prera, C. Abad, E. Vicente, J.L. Gonzalez-Sala, N. Hannaoui, M. Capdevila, L. De Verdonces, A. Ferran, C. Pla, P. Azuara, S. Cuadrench, M.E. Zegri, J. Prats
Journal: European Urology (2022)
Post-receptor signaling by G protein-coupled, contractile receptors is a prerequisite for cytoskeletal organization and cell proliferation in human prostate smooth muscle cells
Authors: A. Tamalunas, A. Wendt, R. Huang, R. Wang, Y. Liu, B. Rutz, A. Ciotkowska, C.G. Stief, M. Hennenberg
Journal: European Urology (2022)
Genomic features of IDH-mutant adult diffuse astrocytoma.
Authors: Hongjun Zhang, Qianqian Duan, Qin Zhang, Yuan Tan, Tingting Sun, Chuang Qi
Journal: Journal of Clinical Oncology (2022)

e14032 Background: The fifth edition of the WHO Classification of Tumors of the Central Nervous System (CNS), published in 2021, which indicated that all IDH mutant diffuse astrocytic tumors are considered a single type (Astrocytoma, IDH-mutant) and are then graded as CNS WHO grade 2, 3, or 4. Besides, the guideline eliminates the term “Glioblastoma (GBM), IDH-mutant”. Moreover, grading is no longer entirely histological, since the presence of CDKN2A/B homozygous deletion results in a CNS WHO grade of 4, even in the absence of microvascular proliferation or necrosis. Therefore, more clinical and genomic characteristics of IDH-mutant astrocytoma under molecular typing need to be further studied. Methods: Adults pathological diagnosed with diffuse astrocytoma and glioblastoma in our Chinese dataset were identified retrospectively. All patients included in the analysis were tested for 131 CNS tumor-related genes (including IDH1/2), chromosomes 1p/19q and chromosomes 7/10. Results: 63 initial diagnosed IDH-mutant diffuse astrocytomas including 46 patients with grade 2-3 and 17 patients with uncertain grade. While, 5.2% of GBM (9/174) harbored IDH1/2 mutation which should be redefined as diffuse astrocytoma, IDH-mutant, WHO 4 grade. And these patients had a high frequency of CDKN2A/B homozygous deletion (88.9%, 8/9). In patients with 2-3 grade and unclear grade, CDKN2A/B homozygous deletion accounted for 18.7% (9/48) and 27.8% (5/18), respectively, which meant the grade of these diffuse astrocytomas should be revised to WHO 4 grade according to guideline. While mutation frequency of crucial prognosis factors in glioma, including chromosomes 7 loss, chromosomes 10 gain, EGFR amplification, PIK3CA/R1, PDGFRA amplification, CDK4 amplification, were 9.7%, 2.8%, 5.6%, 13.9%, 6.9% and 8.3% in all 72 astrocytomas, respectively. In addition, we found 83.3% (5/6) KDR copy number variant were occurred in which initially pathological diagnosed as IDH-mutant GBM. Conclusions: we conducted comprehensive analysis of IDH mutant diffuse astrocytoma. CDKN2A/B homozygous deletion as a specific grade-classified molecular marker could better re-distinguish about 20%-30% 2-3 grade and uncertain grade astrocytoma. KDR copy number variant may be a marker in IDH-mutant astrocytoma to identify the tumor which pathology is closer to GBM.
MODL-15. High-throughput combination drug screening identifies synergism between retinoic acid treatment and BCL-XL-inhibition in <i>MYC(N)</i>-driven medulloblastoma and neuroblastoma models
Authors: Till Seiboldt, Constantia Zeiser, Rabia Salem-Altintas, Duy Nguyen, Tim Holland-Letz, Heike Peterziel, Olaf Witt, Ina Oehme
Journal: Neuro-Oncology (2022)

Abstract PURPOSE: Despite remarkable improvements in childhood cancer survival, certain high-risk entities including malignancies of the nervous system still carry dismal prognoses. Retinoic acid (RA) treatment has long been administered in high-risk neuroblastoma patients and preclinical data suggest a benefit in applying retinoids in selected brain tumor entities. However, limited single-agent efficacy and developing treatment resistance provide a rationale for investigating improved combination treatments. METHODS: We assessed the RA sensitivity of 16 cell lines and patient-derived cultures of pediatric nervous system tumors from the INFORM (INdividualized Therapy FOr Relapsed Malignancies in Childhood) registry. Bulk RNA sequencing was performed for five sensitive models undergoing RA treatment. All models were screened for drug sensitivity to 76 clinically relevant drugs alone and combined with RA. Beneficial hit combinations were further investigated for synergy, as well as their effect on differentiation and apoptosis by high-content fluorescence microscopy and caspase activity assay. Results from in vivo experiments are pending. RESULTS: Group 3 medulloblastoma and high-risk neuroblastoma models were most sensitive to RA treatment leading to significant changes in gene expression of apoptotic regulation. Drug sensitivity screening revealed similar patterns of response to combination treatments in MYC-driven Group 3 medulloblastomas and MYCN-amplified neuroblastomas. Apoptosis regulating BCL-XL-inhibitors (A-1155463, navitoclax) were identified as top hits across RA sensitive models, whereas epigenetic BET family inhibitor I-BET151 and histone deacetylase inhibitor entinostat suggested entity-specific combination benefits in neuroblastoma and medulloblastoma models, respectively. In both entities, combining RA with navitoclax was synergistic and significantly increased caspase-3 activity. The combination led to a morphological shift from differentiation under RA treatment to cell death. CONCLUSION: Exploring combinations for RA treatment in pediatric nervous system tumors, we found that MYC(N)-driven medulloblastoma and neuroblastoma not only share responsiveness to RA treatment, but also demonstrate enhanced vulnerability in combination with BCL-XL-inhibition resulting in increased apoptosis.
<i>BRAF</i>-Mutated Advanced Colorectal Cancer: A Rapidly Changing Therapeutic Landscape
Authors: Kristen K. Ciombor, John H. Strickler, Tanios S. Bekaii-Saab, Rona Yaeger
Journal: Journal of Clinical Oncology (2022)

-mutated advanced colorectal cancer is a relatively small but critical subset of this tumor type on the basis of prognostic and predictive implications.
Identification of small-molecule ERBB4 agonists for the treatment of heart failure
Authors: E Feyen, J Cools, J Van Fraeyenhove, M Tubeeckx, H De Winter, D Audenaert, GW De Keulenaer, VF Segers
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): Dehousse fellowship Introduction Although progress has been made in the treatment of heart failure, morbidity and mortality remain high, requiring new therapeutic targets. The neuregulin-1 (NRG1)/ERBB4 axis is cardioprotective and antifibrotic when activated in the myocardium, and therefore a possible target for therapy. Phase 2 and 3 clinical trials with NRG1 are ongoing, but require intravenous administration regimens, limiting applicability and efficacy. Purpose To develop small-molecule ERBB4 agonists with cardioprotective and antifibrotic properties. Methods A high-throughput screening (HTS) of 10,240 compounds was performed on a ERBB4/ERBB4 dimerization assay. Hit compounds were co-administered with NRG1 or fluorescently labeled NRG1 to determine competitive binding. Selectivity, receptor phosphorylation, cell proliferation and toxicity were determined using Luminex RTK phosphoprotein, ERBB2/ERBB3 dimerization, WST-1 colorimetric, and adenylate kinase assays. Antifibrotic effects were studied in vitro on TGF-β-induced collagen synthesis in human dermal and atrial fibroblasts, and in a mouse model of angiotensin II (AngII, 1000 ng/kg/min)-induced left ventricular (LV) myocardial fibrosis with selected compounds (83 µg/kg/h), administrated with osmotic minipumps (N=4–5/group). mRNA expression was evaluated after 7 days; LV myocardial fibrosis area, cardiomyocyte cross sectional area (CSA), echocardiographic parameters and heart- to bodyweight ratio (HW:BW) were analyzed at 28 days. Antiapoptotic effects were studied on rat atrial cardiomyocytes (AM) after hydrogen peroxide (H2O2)-induced cardiotoxicity. Results The HTS (Z’=0.7) resulted in 8 similar pyrimidine derivatives (EF-1–8) inducing ERBB4/ERBB4 dimerization (Emax 9–33% relative to NRG1, EC50 6E-6 to 2E-7 M). Competition assays indicate allosteric binding. The compounds also significantly potentiated NRG1-induced ERBB4 receptor dimerization up to 2.7 fold. Two compounds were excluded because of in vitro toxicity. The other 6 compounds were non-toxic and induced ERBB4, but neither ERBB1, ERBB2 or ERBB3 phosphorylation, nor tumor growth–inducing ERBB2/ERBB3 dimerization. Selected compounds showed significant dose-dependent antiapoptotic properties on H2O2-stimulated AM, and antifibrotic effects on human atrial and dermal fibroblasts. In vivo, compound EF-1 significantly decreased myocardial fibrosis (by 76±26%) and Col1a1, Col3a1 (-70±17%; -61±20%), and Nppa (-78±32%) mRNA expression, and significantly enhanced cardiomyocyte CSA (+24±8%). No differences were observed in cardiac function or HW:BW ratio. Conclusion We identified novel pyrimidine derivative small-molecule ERBB4 agonists with cardiomyocyte protective effects and antifibrotic properties in vitro and in AngII-induced myocardial fibrosis in vivo.
Breast density reduction as a predictor for prognosis in premenopausal women with hormone receptor–positive breast cancer: A retrospective analysis of the ASTRRA study.
Authors: Soong June Bae, Hyun-Ah Kim, Jai Min Ryu, Seho Park, Eun-Gyeong Lee, Seock-Ah Im, Yongsik Jung, Min Ho Park, Kyong Hwa Park, Su Hwan Kwang, Eunhwa Park, Sung Yong Kim, Min Hyuk Lee, Lee Su Kim, Anbok Lee, Woo Chul Noh, Sei-Hyun Ahn, Seonok Kim, Hee Jeong Kim, Joon Jeong
Journal: Journal of Clinical Oncology (2022)

531 Background: While the relationship between mammographic breast density (MD) decline and anti-hormone therapy efficacy has been reported in estrogen-receptor (ER)-positive breast cancer, it is still unclear in premenopausal women and in the case of adding ovarian function suppression (OFS) to anti-hormone therapy. We aimed to investigate the MD reduction (MDR) rate and impact of MDR on prognosis stratified by treatment from the updated result of the ASTRRA trial. Methods: ASTRRA trial, a randomized phase 3 study, showed that adding ovarian function suppression (OFS) to tamoxifen (TAM) improved survival in premenopausal women with ER+ breast cancer after chemotherapy. We updated survival outcomes with a median follow-up of 108 months. We assessed mammography taken before treatment and the follow-up mammography taken annually for up to five years after initiation of treatment. MD was classified into four categories based on the Breast Imaging Reporting and Data System. MDR positivity was defined as a downgrade in MD among follow-up mammography up to two years after randomization, with the pretreatment MD grade as a reference. Results: Among the 1,293 patients from ASTRRA trial, we successfully evaluated MDR in 947 patients, of which 796 (83.4%) belong to high MD (grade C or D). The patient characteristics were similar between the entire ASTRRA trial and the subgroup with available MDR. There was no difference in MDR-positive rate between two treatment groups (106 of 477 [22.2%] in TAM-only group vs. 87 of 470 [18.5%] in TAM + OFS group, P =.156). MDR-positivity was significantly associated with better disease-free survival (DFS) in TAM + OFS group (estimated 8-year DFS: 92.9% in MDR-positive vs. 82.2% in MDR-negative, P =.013), but did not in TAM-only group (estimated 8-year DFS: 80.3% in MDR-positive vs. 80.2% in MDR-negative, P =.927; P interaction =.025). Simialr trends were observed in terms of recurrence-free survival, distant metastasis-free survival (DMFS), locoregional-free survival, and overall survival. In addition, MDR-positivity was an independent factor for favorable DFS (adjusted hazard ratio [HR], 0.37; 95% CI, 0.16 to 0.86; P =.021) and DMFS (adjusted HR, 0.35; 95% CI, 0.13 to 0.98; P =.045) in TAM + OFS group. Conclusions: Although the proportion of patients with MDR-positive was comparable between the two treatment groups, MDR-positive was independently associated with favorable outcomes only in TAM + OFS group. Future work is warranted to verify the mechanism by which the association between MDR and clinical benefit differs according to the treatment group. Clinical trial information: NCT00912548.
LGG-40. Growth hormone replacement in children on therapy with Vemurafenib for Low Grade Glioma
Authors: Antonio Verrico, Marco Crocco, Emilio Casalini, Antonia Ramaglia, Andrea Rossi, Valentina Iurilli, Gianluca Piccolo, Claudia Milanaccio, Maria Luisa Garrè, Natascia Di Iorgi
Journal: Neuro-Oncology (2022)

Abstract BRAF inhibitors (iBRAF) are a therapeutical option for pediatric Low-Grade-Gliomas (pLGG), but their chronic use may be needed to prevent tumor regrowth. Growth hormone (GH) replacement in children with GH deficiency (GHD) and on oncological treatment is under debate. We report on our experience of recombinant human GH (rhGH) replacement in two children (1 Female, 1 Male) which started Vemurafenib therapy, at 5 (F) and 9,25 (M) years of age, for recurrent/progressive chiasmatic-hypothalamic pLGG, with partial response (RANO criteria) and subsequent stable disease. A diagnosis of GHD was established at 9,2 (F) and 11,2 (M) years of age (GH peaks to stimulation tests &amp;lt;3mcg/L), 4,2 (F) and 1,9 (M) years after Vemurafenib start. Both patients were treated with GnRH analogues for precocious puberty. rhGH dose was titrated to 0.020 mg/kg/day during follow-up based on IGF-1 levels &amp;lt; +2 SDS. Height remained stable in both (F: -3,4SDS; M: 0SDS), with a mean growth velocity after 2 years around 6 cm/yr. BMI increased in the F (1,59 to 1,78 SDS) and decreased in the M (2,66 to 2,56 SDS); Dual-X-ray absorbiometry confirmed high fat mass at T0 (F:54,6%; M:48%) and at T24 (F:49,2%; M:48,1%). Lipid profile improved in both patients (F: Triglycerides 175 to 152 mg/dl, LDL 195 to 155 mg/dl; M: Triglycerides 138 to 118 mg/dl, LDL 147 to 147 mg/dl, at T0 and T24, respectively), while baseline blood glucose increased (F: 83 to 96 mg/dl; M 82 to 91 mg/dl). Residual tumor was stable in both patients. CONCLUSIONS: In 2 GHD patients due to pLGG and treated with Vemurafenib, two-years of low-dose rhGH showed beneficial effects on height stabilization and on lipid profile, and a different impact on body composition parameters; rhGH was safe and not associated with residual tumor growth.
Fertility preservation decisions and outcomes of young women with breast cancer.
Authors: Devora Isseroff, Bridgette Thom, Cassandra Chang, Nadia Abdo, Rosemary Semler, Mary Gemignani, Joanne Frankel Kelvin, Shari Beth Goldfarb
Journal: Journal of Clinical Oncology (2022)

e12520 Background: As breast cancer (BC) survival improves, fertility preservation (FP) counselling prior to initiating gonadotoxic chemotherapy for women of child-bearing age becomes more important. This study explores the factors that influence the decisions to pursue FP before and after breast cancer treatment and the FP outcomes. Methods: An IRB approved web-based survey examining decisions about FP, factors influencing decisions, and post-decision regret was administered to English and Spanish speaking women (age 18-45) diagnosed with stage I-III BC. All women received education and counselling by a MSK Fertility Nurse Specialist prior to initiating cancer treatment at MSKCC in 2009-2017. Additional data was extracted from the medical record. Results: 211 women with BC (82% ER+, 19% HER-2+, 12% triple negative) with a mean age of 34 (age range 20-45) participated in this study. At the time of diagnosis 128 (61%) women were married/living with partner and 46 (22%) women had children. 151 (72%) wanted (additional) children, 48 (23%) were unsure if they wanted (additional) children and 12 (6%) did not want (additional) children. Of the 151 women who desired (additional) children, 94 underwent FP pre-treatment and 3 post-treatment. Of 48 unsure women, 14 underwent FP. A total of 115 women underwent FP before treatment: 73 froze eggs and 49 froze embryos. After treatment 28 (13%) women met with a reproductive endocrinologist and 13 underwent FP: 9 froze eggs and 4 froze embryo. The average number of eggs frozen was 14 pre-treatment and 18 post-treatment. The average number of embryos frozen was 7 both pre- and post-treatment. After completing primary breast cancer treatment, 61 women opted to try to build their family and 42 had children: 35 gave birth and 7 used a surrogate. In a multivariate analysis lower socioeconomic status and non-white race were predictive of discordance between desire for FP and completion of FP before treatment (p &lt; 0.05). 65% of patients reported cost of freezing eggs/embryos was important in their decision. Insurance did not cover any FP treatment for 56/115 (49%) of women and 34% (39/115) of women paid $10,000 or more for their FP. Participants reported the ability to feel hopeful about their future (82%) and fear of regret (80%) were the most important factors when making their FP decision. 83% (176/211) of women believe they made the right FP decision and 80% would make the same decision again. Women had less regret if they underwent FP. Conclusions: Our study demonstrates the importance of discussing FP with women with BC of child-bearing age, regardless of race or economic status. Fertility preservation is often successful in women with BC. Regardless of pregnancy outcomes, women felt that having FP offered them a sense of control and hope for the future during a vulnerable time in their lives with low risk of regret.
QOL-08. Visual memory and potential clinical risk factors in long-term survivors of a childhood brain tumor
Authors: Charlotte Sleurs, Jurgen Lemiere, Kristien Bullens, Sandra Jacobs
Journal: Neuro-Oncology (2022)

Abstract A brain tumor treatment has previously been associated with long-term neurocognitive sequelae. However, clinical profiles differ between certain patient subgroups. We investigated the impact of tumor location, radiotherapy (RT), and age at diagnosis in childhood brain tumor survivors on long-term cognitive outcomes. Adult survivors (n=32) of pediatric brain tumors (n=11 infratentorial, n=21 supratentorial; 14 astrocytomas, 3 craniopharyngiomas, 2 ependymomas, 2 germinomas, 1 hemangioblastomas, 4 medulloblastomas, 6 nervus opticus gliomas) participated in this neuropsychological study (n=11 RT) (16.8-35.1 years old, &amp;gt;2years after treatment, mean age at diagnosis = 9.2 years, 50% male). An extensive neurocognitive test battery was used to assess intelligence scales (n=5), verbal and visual memory (n=2), and language (n=3). In order to investigate the effects of tumor location (infra- versus supratentorial), RT (yes vs. no), and age at diagnosis on the cognitive scores, a multivariate ANCOVA model was tested including the main effects and interaction between age and RT. Of all included scales, only visual memory was significantly associated with the risk factors. More specifically, patients who received RT (F=10.3, p=.004) and were younger at diagnosis (F=6.9, p=.014) scored worse on this task. Furthermore, the interaction effect between these factors was also significant (F=8.8, p=.006). These findings suggest that younger patients could be more vulnerable to the radiotoxic effects to visual memory outcomes. Tumor location (supra- vs. infratentorial) was not significantly associated with any outcome. In this study, only visual memory appeared to be associated with the risk factors of interest. Both radiotherapy and age at radiotherapy, as well as their interaction, could be risk factors for altered neurodevelopmental patterns of brain areas associated with visual memory.
HGG-46. Inter and Intra-tumor Heterogeneity of Pediatric-type Diffuse High-Grade Glioma Revealed by High-Dimensional Single-Cell Proteomics
Authors: Lucia Lisa Petrilli, Claudia Fuoco, Luca Pasquini, Alessandro Palma, Giulia Pericoli, Yura Grabovska, Alan Mackay, Sabrina Rossi, Francesca Diomedi Camassei, Angel Montero Carcaboso, Andrea Carai, Angela Mastronuzzi, Chris Jones, Gianni Cesareni, Franco Locatelli, Maria Vinci
Journal: Neuro-Oncology (2022)

Abstract Paediatric-type diffuse high-grade gliomas (PDHGG) are aggressive brain tumors, affecting children and young adults, with no effective treatments. A main constraint to the development of effective treatment is associated with their highly heterogeneous nature. In order to further dissect their intra and inter tumor heterogeneity, we exploited the mass cytometry technology, an advanced -OMIC approach that, by using metal-tagged antibodies, allows the simultaneous measurement of more than 40 markers, at single-cell level. Here we characterized 8 primary cell lines derived from diffuse pediatric-type high-grade glioma H3-wildtype (DHGG-WT), Diffuse hemispheric glioma H3G34-mutant (DHG-G34) and Diffuse midline glioma H3K27-altered (DMG-K27) patients. The adopted antibody panel was set to recognize antigens expressed by brain and tumor cells, including H3K27M and H3.3G34R variants, and it highlighted important intra- and inter- tumor heterogeneity in the expression of the 16 considered markers. Of these, CD56, CD44, CD29 and NESTIN were more expressed in the hemispheric cell lines, while CD90 was more expressed in the pontine. Even if there was not always a concordance between CyTOF and mRNA expression data from cell lines and tumor samples (e.g. CD90 and GFAP), CyTOF data were in line with the immunohistochemistry analysis for GFAP, whose expression was significantly higher in H3.1K27 compared to H3.3K27. The UMAP analysis allowed us to identify 10 cell clusters, with very minimal overlap between hemispheric and pontine location subgroups and with a peculiar antigenic profile, whose abundance strongly varied according to the mutational subgroups. For example, while the G34 subgroup was enriched for cluster 9 (CD29/CD63/CD56/PDGRFa), the H3.1K27 was enriched for cluster 3 (H3K27M/CD90/CD63/CD56) and cluster 4 (H3K27M/CD63/CD90/CD56/GFAP). In conclusion, single-cell mass cytometry reveals a significant inter and intra-tumoral heterogeneity at protein level, dependent on the molecular alterations. This approach could contribute to the identification of new clinically relevant biomarkers for PDHGG.